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More On Reproducing Scientific Results: Organic Chemistry Edition
Yesterday’s post on reproducing scientific results got me to thinking about the application of this to organic chemistry. How much of this are we going to see, compared to biology?
Not as much, is my guess. Some of the barriers to reproducibility are too low to bother with, while others are too high. In the “too low” category are many new synthetic method papers. People try these things out, if they look useful at all, and they either work or they don’t. Most of the time, you end up finding the limits of the reported method – your substrate failed dismally, but when you look, you realize that you had a basic tertiary amine in your molecule, and none of the examples in the paper have one. Ah-hah.
It’s rare that a useful-looking reaction turns out to be completely non-reproducible across multiple structures (although it has happened). Here’s a paper from 2000, by one Vincent C. O. Njar, claiming that carbonyl diimidazole reacted with hydroxy groups to give direct N-alkylation of imidazole. Two years later, Walter Fischer from Ciba Specialty Chemicals took this paper apart in detail, showing that it did not work and could not have worked. The products were carbamates instead – not surprising – and the original author should have realized this (as should the referees of the paper).
Then you have total synthesis. And here, the barrier is too high: no one is going to reproduce these things after a certain point. A 48-step synthesis of Shootmenowicene could appear tomorrow, and the odds are overwhelming that no one will ever explore its heights again. There have been total syntheses that have been received with grave doubts (hexacyclinol!), but no one, to the best of my knowledge, has gone back over every step of one of these. The return on the investment of time and money is just too low – which, to be frank, is a sentence that sums up my opinion of a lot of total synthesis work these days.
Where the Reproducibility Initiative could come in handy inside organic chemistry, though, would be for unusual things of wide applicability that are still hard to believe. The famous “NMR chirality” scandal at the University of Bonn in the 1990s would be a good example of this. This was a startling result – that the chirality of organic reactions could be measurably influenced by the handedness of an applied magnetic field – and many people had trouble believing it on physical grounds. They were right, too, because it all turned out to be faked by an individual inside the group, a fact that was only discovered after much effort and embarrassment. Having immediate access to third-party reproducibility testing would have sped things up quite a bit – and perhaps if that access is more widely known, used, and appreciated, we might see fewer bizarre cases like this in general.
Derek Lowe is a medicinal chemist with over 20 years experience in the drug industry. He blogs daily on science and drug discovery at In The Pipeline
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